The Role of Oxidative Stress in Hyperuricemia and Xanthine Oxidoreductase (XOR) Inhibitors

Figure 1

Purine metabolism. Adenosine monophosphate (AMP) is converted to inosine by forming inosine monophosphate (IMP) as an intermediate by AMP deaminase, or by nucleotidase to form adenosine followed by purine nucleoside phosphorylase (PNP) to form adenine; simultaneously, guanine monophosphate (GMP) is converted to guanosine by nucleotidase followed by PNP to form guanine. Moreover, AMP and GMP also have feedback regulation on 5-phosphoribosyl-1-pyrophosphate (PRPP). Hypoxanthine is oxidized to form xanthine by XOR which includes XDH and XO, and the conversion of guanine to xanthine occurs through the action of guanine deaminase. The enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT) salvages hypoxanthine to IMP and GMP. In a similar salvage pathway, adenine phosphoribosyl transferase (APRT) converts adenine to AMP. Finally, XOR catalyzes the oxidation of xanthine to uric acid, with the accompanying production of ROS. In most mammalian species such as rats and mice, uric acid generated from purine metabolism is further degraded into allantoin by uricase, an enzyme that is mostly found in the liver. However, in humans and the great apes, uric acid is the endpoint of purine metabolism because the uricase gene is crippled. It is estimated that approximately 30% of uric acid excretion is by the intestine and renal mechanisms of urate excretion account for the other 70%.